Drug resistance has been an ever-lasting obstacle in treatment of refractory rheumatoid arthritis (refractory RA). Resistance to classical therapeutic agents could be classified into two major categories: intrinsic resistance that is genetically caused, and acquired resistance that develops as consequence of selective pressure under drug exposure. In fact, intrinsic drug resistance is more frequently found in inflammatory diseases, e.g. rheumatoid arthritis (RA). For instance, rheumatoid arthritis synovial fibroblasts (RASFs) exhibit apoptosis-resistance which is due to low level expression of TNF-related apoptosis-inducing ligand (TRAIL) death receptors. Such an apoptosis-resistant phenotype is considered as a major characteristic of the refractory cases of RA. RASFs also exhibits “tumor-like” phenotype, these cells have been re-conceptualized from passive structural cells to invasive, destructive, immunogenic, hyperplastic cells exhibiting multipotent inflammatory properties which contribute to the pathology of RA. The synovial environment in RA favours survival of RASFs and discourages their removal through apoptosis.
Apart from apoptotic proteins, the tumor suppressor p53 is a sensor of cellular stress and also a critical initiator of apoptosis. Generally, the high frequency of p53 mutations eventually leads to chemo-resistance of cancer cells. Surprisingly, somatic mutations of p53 are frequently identified in synovia of patients suffering from RA. In particular, dominant-negative p53 mutation of N239S and R213* contributes to apoptosis inhibition and inflammatory cytokine production. These findings suggest that p53 mutations may be involved in the mechanism of developing refractory RA.
Furthermore, patients suffering from refractory RA may exhibit multidrug resistance (MDR). Such a multidrug resistance may be intrinsic or acquired resistance. The MDR phenotype confers unresponsiveness to many diverse dugs by drug efflux, which may be mediated by ABC transporter protein. ABC transporter proteins have been found to be constitutively expressed and overexpressed, respectively, in many multidrug-resistant disease, wherein P-glycoprotein is considered for being a key player in the multidrug-resistant phenotype. P-glycoprotein (P-gp), a 170-kd ATP-dependent membrane transporter, which reduces intracellular drug concentrations to sub-optimal levels. Maillefert J F et al., Br J Rheumatol 1996 (35), reported that the percentage of peripheral blood lymphocytes expressing P-gp was significantly higher in RA patients treated with prednisolone, these might cause efflux of corticosteroids and disease-modifying anti-rheumatic drugs (DMARDs) from lymphocytes, and eventually develop drug-resistance in patients with severe inflammatory condition.
Consequently, there is a strong need for methods and means allowing for an effective therapeutic treatment especially of refractory rheumatoid arthritis and multidrug-resistant rheumatoid arthritis synovial fibroblasts, respectively. In particular, efficacious treatment options are urgently required for specifically treating subjects with refractory rheumatoid arthritis with expression or overexpression of ABC transporter proteins or decreased expression of pro-apoptotic proteins and increased expression of anti-apoptotic proteins, respectively, i.e. for treating said specific subgroups of subjects among subjects with rheumatoid arthritis.